Ruxolitinib attenuates diethylnitrosamine-induced liver injury in mice: involvement of TLR4/MYD88/NF-κB and IL-6/JAK/STAT pathways.

The liver is a main target organ for xenobiotic-induced acute injury, with such toxicity frequently mediated through the oxidative stress generation and the subsequent activation of inflammatory signaling pathways like TLR4/MYD88/NF-κB and IL-6/JAK/STAT pathways. The current study investigated the potential protective effect of ruxolitinib (RUX) on liver injury induced by diethylnitrosamine (DEN). Mice were administered RUX prophylactically as a single dose orally, then DEN (150 mg/kg, i.p.) after an hour. Interestingly, RUX significantly alleviated liver injury induced by DEN as evidenced by marked improvement in liver architecture as illustrated in H&E-stained liver sections besides reduced blood levels of LDH, ALT and AST. Moreover, RUX restored cellular reserve of reduced glutathione (GSH) and hindered peroxidation of lipid and nitrosative stress as evidenced by dampened malondialdehyde (MDA) and nitric oxide (NO), respectively. Mechanistically, RUX down regulated both IL-6/JAK2/STAT3 and TLR4/MYD88/NF-κB pathways. IL-6/JAK2/STAT3 pathway has an important role in inflammation as it regulates many inflammatory cytokines' expression. Also, TLR4/MYD88/NF-κB pathway is another inflammatory pathway that induces release of pro-inflammatory cytokines. In summary, DEN-induced liver injury was mitigated by RUX by suppressing JAK2, which might be a promising tool for prohibiting liver injury induced by DEN or other exogenous chemicals.